Management of Management of overdose and overdose and poisoning poisoning
Paula Jerrard-DunnePaula Jerrard-DunnePharmacology & Therapeutics Pharmacology & Therapeutics 20062006
General- evaluationGeneral- evaluation
recognition of poisoningrecognition of poisoning identification of agents involved identification of agents involved assessment of severity assessment of severity prediction of toxicity prediction of toxicity
General- managementGeneral- management
provision of supportive careprovision of supportive care prevention of poison absorptionprevention of poison absorption enhancement of elimination of enhancement of elimination of
poisonpoison administration of antidotes administration of antidotes
Supportive careSupportive care
ABCABC Vital signs, mental status, and pupil size Vital signs, mental status, and pupil size Pulse oximetry, cardiac monitoring, ECGPulse oximetry, cardiac monitoring, ECG Protect airwayProtect airway Intravenous access Intravenous access cervical immobilization if suspect traumacervical immobilization if suspect trauma Rule out hypoglycaemiaRule out hypoglycaemia Naloxone for suspected opiate poisoningNaloxone for suspected opiate poisoning
HistoryHistory
Pill bottlesPill bottles AlcoholAlcohol Drug history including accessDrug history including access Remember OTC drugsRemember OTC drugs Suicide noteSuicide note National Poisons Information National Poisons Information
Centre *Centre *
ExaminationExamination
Physiologic excitation –Physiologic excitation – anticholinergic, sympathomimetic, or central anticholinergic, sympathomimetic, or central
hallucinogenic agents, drug withdrawalhallucinogenic agents, drug withdrawal Physiologic depression –Physiologic depression – cholinergic (parasympathomimetic), cholinergic (parasympathomimetic),
sympatholytic, opiate, or sedative-hypnotic sympatholytic, opiate, or sedative-hypnotic agents, or alcohols agents, or alcohols
Mixed state –Mixed state –
polydrugs, polydrugs, hypoglycemic agents, tricyclic hypoglycemic agents, tricyclic antidepressants, salicylates, cyanideantidepressants, salicylates, cyanide
Drug detectionDrug detection
Drug levelsDrug levels
Preventing absorptionPreventing absorption
Gastric lavageGastric lavage Not in unconscious patient unless intubated (risk aspiration)Not in unconscious patient unless intubated (risk aspiration)
Flexible tube is inserted through the nose into the stomach Flexible tube is inserted through the nose into the stomach
Stomach contents are then suctioned via the tubeStomach contents are then suctioned via the tube
A solution of saline is injected into the tube A solution of saline is injected into the tube
Recommended for up to 2 hrs in TCA & up to 4hrs in Recommended for up to 2 hrs in TCA & up to 4hrs in
Salicylate ODSalicylate OD
Induced VomitingInduced Vomiting Ipecac - Not routinely recommended Ipecac - Not routinely recommended Risk of aspirationRisk of aspiration
Preventing absorptionPreventing absorption
Activated charcoalActivated charcoal Adsorbs toxic substances or irritants, thus inhibiting GI Adsorbs toxic substances or irritants, thus inhibiting GI
absorption absorption Addition of sorbitol Addition of sorbitol →→laxative effectlaxative effect Oral: 25-100 g as a single dose Oral: 25-100 g as a single dose repetitive doses useful to enhance the elimination of repetitive doses useful to enhance the elimination of
certain drugs (eg, theophylline, phenobarbital, certain drugs (eg, theophylline, phenobarbital, carbamazepine, aspirin, sustained-release products)carbamazepine, aspirin, sustained-release products)
not effective for cyanide, mineral acids, caustic alkalis, not effective for cyanide, mineral acids, caustic alkalis, organic solvents, iron, ethanol, methanol poisoning, organic solvents, iron, ethanol, methanol poisoning, lithium lithium
Elimination of poisonsElimination of poisons
Renal eliminationRenal elimination Medication to stimulate urination or defecation may be given to Medication to stimulate urination or defecation may be given to
try to flush the excess drug out of the body faster.try to flush the excess drug out of the body faster.
Forced alkaline diuresisForced alkaline diuresis Infusion of large amount of NS+NAHCO3Infusion of large amount of NS+NAHCO3 Used to eliminate acidic drug that mainly excreted by the kidney Used to eliminate acidic drug that mainly excreted by the kidney
eg salicylateseg salicylates Serious fluid and electrolytes disturbance may occurSerious fluid and electrolytes disturbance may occur Need expert monitoringNeed expert monitoring
Hemodialysis or haemoperfusionHemodialysis or haemoperfusion: : Reserved for severe poisoning Reserved for severe poisoning Drug should be dialyzable i.e. protein bound with low volume of Drug should be dialyzable i.e. protein bound with low volume of
distributiondistribution may also be used temporarily or as long term if the kidneys are may also be used temporarily or as long term if the kidneys are
damaged due to the overdose. damaged due to the overdose.
Antidotes Antidotes
Does an antidote exist?Does an antidote exist? Does actual or predicted severity Does actual or predicted severity
of poisoning warrant its use?of poisoning warrant its use? Do expected benefits of therapy Do expected benefits of therapy
outweigh its associated risk?outweigh its associated risk? Are there contraindications? Are there contraindications?
Specific overdosesSpecific overdoses
OpiatesOpiates
Antidote – naloxoneAntidote – naloxone MOA: Pure opioid antagonist competes and MOA: Pure opioid antagonist competes and
displaces narcotics at opioid receptor sites displaces narcotics at opioid receptor sites I.V. (preferred), I.M., intratracheal, SubQ: 0.4-2 mg I.V. (preferred), I.M., intratracheal, SubQ: 0.4-2 mg
every 2-3 minutes as needed every 2-3 minutes as needed Lower doses in opiate dependenceLower doses in opiate dependence Elimination half-life of naloxone is only 60 to 90 Elimination half-life of naloxone is only 60 to 90
minutes minutes Repeated administration/infusion may be Repeated administration/infusion may be
necessarynecessary
S/E BP changes; arrhythmias; seizures; withdrawalS/E BP changes; arrhythmias; seizures; withdrawal
BenzodiazepinesBenzodiazepines
Antidote – flumazenilAntidote – flumazenil MOA: Benzodiazepine antagonist MOA: Benzodiazepine antagonist IV administration 0.2 mg over 15 sec to max IV administration 0.2 mg over 15 sec to max
3mg3mg S/E N&V; arrhythmias; convulsionsS/E N&V; arrhythmias; convulsions C/I concomitant TCAD; status epilepticusC/I concomitant TCAD; status epilepticus Should not be used for making the diagnosisShould not be used for making the diagnosis Benzodiazepines may be masking/protecting Benzodiazepines may be masking/protecting
against other drug effectsagainst other drug effects
Tricyclic Tricyclic antidepressantsantidepressants PHARMACOLOGYPHARMACOLOGY — — TCAs have several important cellular effects, including TCAs have several important cellular effects, including
inhibition of:inhibition of:
Presynaptic neurotransmitter reuptakePresynaptic neurotransmitter reuptake
Cardiac fast sodium channels Cardiac fast sodium channels
Central and peripheral muscarinic acetylcholine receptors Central and peripheral muscarinic acetylcholine receptors
Peripheral alpha-1 adrenergic receptors Peripheral alpha-1 adrenergic receptors
Histamine (H1) receptors Histamine (H1) receptors
CNS GABA-A receptors CNS GABA-A receptors
TCAD overdoseTCAD overdoseclinical featuresclinical features
Arrhythmias Arrhythmias
- widening of PR, QRS, and QT intervals; - widening of PR, QRS, and QT intervals;
heart block; VF/VTheart block; VF/VT
HypotensionHypotension
Anticholinergic toxicity Anticholinergic toxicity
- - hyperthermia, flushing, dilated pupils, hyperthermia, flushing, dilated pupils,
intestinal ileus, urinary retention, sinus tachycardiaintestinal ileus, urinary retention, sinus tachycardia
Confusion, delirium, hallucinationsConfusion, delirium, hallucinations
Seizures Seizures
DiagnosisDiagnosis
HistoryHistory
Blood/urine toxicology screenBlood/urine toxicology screen
Levels not clinically usefulLevels not clinically useful
TCAD overdose -TreatmentTCAD overdose -Treatment
ABC – many require intubationABC – many require intubation Consider gastric lavage if taken < 2hrsConsider gastric lavage if taken < 2hrs Activated charcoalActivated charcoal Treatment of hypotension with isotonic salineTreatment of hypotension with isotonic saline Sodium bicarbonateSodium bicarbonate for cardiovascular toxicity for cardiovascular toxicity Alpha adrenergic vasopressors (Alpha adrenergic vasopressors (
norepinephrinenorepinephrine) for hypotension refractory to ) for hypotension refractory to
aggressive fluid resuscitation and bicarbonate aggressive fluid resuscitation and bicarbonate
infusion infusion Benzodiazepines for seizuresBenzodiazepines for seizures
Sodium Bicarbonate Sodium Bicarbonate in TCA in TCA overdoseoverdose Hypertonic Hypertonic sodium bicarbonatesodium bicarbonate (NaHCO3) (NaHCO3)
- QRS widening >100 msec; ventricular - QRS widening >100 msec; ventricular
arrhythmias, and/or refractory hypotension arrhythmias, and/or refractory hypotension
↑↑ serum pH promotes protein binding and serum pH promotes protein binding and ↓↓ free drug free drug
concentrations; narrows the QRS complex, concentrations; narrows the QRS complex, ↑↑ systolic blood systolic blood
pressure, and controls ventricular arrhythmiaspressure, and controls ventricular arrhythmias
1 to 2 meq/kg (two to three 100 mL ampules of 8.4 percent 1 to 2 meq/kg (two to three 100 mL ampules of 8.4 percent
NaHCO3) rapid IV push large bore IV then infusion if workingNaHCO3) rapid IV push large bore IV then infusion if working
reasonable goal pH is 7.50 to 7.55 then taper dosereasonable goal pH is 7.50 to 7.55 then taper dose
S/E S/E Volume overload, hypernatreamia, and metabolic alkalosis Volume overload, hypernatreamia, and metabolic alkalosis
Special Cautions in TCAD Special Cautions in TCAD overdoseoverdose
Class IA and IC antiarrhythmic agents are Class IA and IC antiarrhythmic agents are
contraindicated eg quinidine;disopyramide, contraindicated eg quinidine;disopyramide,
flecainide; propafenoneflecainide; propafenone
Class IB Lignocaine, phenytoin usedClass IB Lignocaine, phenytoin used
Phenytoin may precipitate arrhythmiasPhenytoin may precipitate arrhythmias
Magnesium may be usefulMagnesium may be useful
Flumazenil must Flumazenil must notnot be given be given
Salicylate overdoseSalicylate overdose
Aspirin (Aspirin (acetylsalicylic acid)acetylsalicylic acid) Methyl salicylate (Oil of Wintergreen)Methyl salicylate (Oil of Wintergreen) 5 ml = 7g salicylic acid5 ml = 7g salicylic acid Herbal remediesHerbal remedies Fatal intoxication can occur after the Fatal intoxication can occur after the
ingestion of 10 to 30 g by adults and ingestion of 10 to 30 g by adults and as little as 3 g by childrenas little as 3 g by children
Salicylate levelsSalicylate levels
Plasma salicylate concentrationPlasma salicylate concentration
Rapidly absorbed; peak blood levels usually Rapidly absorbed; peak blood levels usually
occur within one hour but delayed in overdose 6-occur within one hour but delayed in overdose 6-
35 hrs 35 hrs
Measure @ 4 hrs post ingestion & every 2 hrs Measure @ 4 hrs post ingestion & every 2 hrs
until they are clearly fallinguntil they are clearly falling
Most patients show signs of intoxication when Most patients show signs of intoxication when
the plasma level exceeds 40 to 50 mg/dL (2.9 to the plasma level exceeds 40 to 50 mg/dL (2.9 to
3.6 mmol/L) 3.6 mmol/L)
Salicylate overdoseSalicylate overdose
Inhibition of cyclooxygenase results in decreased synthesis of Inhibition of cyclooxygenase results in decreased synthesis of
prostaglandins, prostacyclin, and thromboxanesprostaglandins, prostacyclin, and thromboxanes Stimulation of the chemoreceptor trigger zone in the medulla Stimulation of the chemoreceptor trigger zone in the medulla
causes nausea and vomitingcauses nausea and vomiting Direct toxicity of salicylate species in the CNS, cerebral edema, Direct toxicity of salicylate species in the CNS, cerebral edema,
and neuroglycopenia and neuroglycopenia Activation of the respiratory center of the medulla results in Activation of the respiratory center of the medulla results in
tachypnea, hyperventilation, respiratory alkalosistachypnea, hyperventilation, respiratory alkalosis Uncoupled oxidative phosphorylation in the mitochondria Uncoupled oxidative phosphorylation in the mitochondria
generates heat and may increase body temperature generates heat and may increase body temperature Interference with cellular metabolism leads to metabolic acidosisInterference with cellular metabolism leads to metabolic acidosis
Clinical featuresClinical features
Early symptoms of Early symptoms of aspirinaspirin toxicity include toxicity include
tinnitus, fever, vertigo, nausea, tinnitus, fever, vertigo, nausea,
hyperventilation, vomiting, diarrhoeahyperventilation, vomiting, diarrhoea
More severe intoxication can cause altered More severe intoxication can cause altered
mental status, coma, non-cardiac pulmonary mental status, coma, non-cardiac pulmonary
oedema and deathoedema and death
Metabolic Metabolic abnormalitiesabnormalities Stimulate the respiratory center directly, early fall in the PCO2 Stimulate the respiratory center directly, early fall in the PCO2
and and respiratory alkalosis respiratory alkalosis
An anion-gap An anion-gap metabolic acidosismetabolic acidosis then follows, due to the then follows, due to the
accumulation of organic acids, including lactic acid and accumulation of organic acids, including lactic acid and
ketoacidsketoacids
Mixed Mixed respiratory alkalosis and metabolic acidosisrespiratory alkalosis and metabolic acidosis with with ↑ anion ↑ anion
gapgap
Arterial Ph variable depending on severityArterial Ph variable depending on severity
Metabolic Metabolic abnormalitiesabnormalities Metabolic acidosis Metabolic acidosis increases the increases the
plasma concentration of plasma concentration of protonated salicylate protonated salicylate
thus worsening toxicity by thus worsening toxicity by allowing easy diffusion of the allowing easy diffusion of the drug across cell membranesdrug across cell membranes
Salicylate overdose - Salicylate overdose - treatmenttreatment
directed toward increasing systemic pH by the directed toward increasing systemic pH by the administration of sodium bicarbonate administration of sodium bicarbonate
IV fluids +/- vasopressorsIV fluids +/- vasopressors
Avoid intubation if at all possible (Avoid intubation if at all possible (↑ acidosis)↑ acidosis)
Supplemental glucose (100 mL of 50 percent dextrose Supplemental glucose (100 mL of 50 percent dextrose in adults) to patients with altered mental status in adults) to patients with altered mental status regardless of serum glucose concentration to regardless of serum glucose concentration to overcome neuroglycopaeniaovercome neuroglycopaenia
HemodialysisHemodialysis
Alkalinization of plasma and Alkalinization of plasma and
urineurine Alkalemia from a respiratory alkalosis is not a Alkalemia from a respiratory alkalosis is not a
contraindication to sodium bicarbonate therapy contraindication to sodium bicarbonate therapy
A urine pH of 7.5 to 8.0 is desirableA urine pH of 7.5 to 8.0 is desirable
Blood gas analysis every two hours Blood gas analysis every two hours
Avoid severe alkalemia (arterial pH >7.60)Avoid severe alkalemia (arterial pH >7.60)
Haemodialysis - indicationsHaemodialysis - indications
Altered mental statusAltered mental status
Pulmonary or cerebral edemaPulmonary or cerebral edema
Renal insufficiency that interferes with salicylate excretionRenal insufficiency that interferes with salicylate excretion
Fluid overload that prevents the administration of sodium Fluid overload that prevents the administration of sodium bicarbonatebicarbonate
A plasma salicylate concentration >100 mg/dL (7.2 mmol/L)A plasma salicylate concentration >100 mg/dL (7.2 mmol/L)
Clinical deterioration despite aggressive and appropriate Clinical deterioration despite aggressive and appropriate supportive caresupportive care
ParacetamolParacetamol
Widely availableWidely available
Potential toxicity underestimatedPotential toxicity underestimated
Toxicity unlikely to result from a single dose of less Toxicity unlikely to result from a single dose of less
than 150 mg/kg in child or 7.5 to 10 g for adult than 150 mg/kg in child or 7.5 to 10 g for adult
Toxicity is likely with single ingestions greater than 250 Toxicity is likely with single ingestions greater than 250
mg/kg or those greater than 12 g over a 24-hour period mg/kg or those greater than 12 g over a 24-hour period
Virtually all patients who ingest doses in excess of 350 Virtually all patients who ingest doses in excess of 350
mg/kg develop severe liver toxicity unless mg/kg develop severe liver toxicity unless
appropriately treatedappropriately treated
Factors influencing Factors influencing toxicitytoxicity Dose ingestedDose ingested
Excessive cytochrome P450 activity due to induction Excessive cytochrome P450 activity due to induction
by chronic alcohol or other drug use eg by chronic alcohol or other drug use eg
carbamazepine, phenytoin, isoniazid, rifampin carbamazepine, phenytoin, isoniazid, rifampin
Decreased capacity for glucuronidation or sulfationDecreased capacity for glucuronidation or sulfation
Depletion of glutathione stores due to malnutrition or Depletion of glutathione stores due to malnutrition or
chronicchronic alcohol ingestion alcohol ingestion
Acute alcohol ingestion is not a risk factor for Acute alcohol ingestion is not a risk factor for
hepatotoxicity and may even be protective by hepatotoxicity and may even be protective by
competing with acetaminophen for CYP2E1 competing with acetaminophen for CYP2E1
Clinical featuresClinical features Stage I (0.5 to 24 hours)Stage I (0.5 to 24 hours)
No symptoms; N&V MalaiseNo symptoms; N&V Malaise
Stage II (24 to 72 hours)Stage II (24 to 72 hours)
Subclinical elevations of hepatic aminotransferases (AST, ALT) Subclinical elevations of hepatic aminotransferases (AST, ALT)
right upper quadrant pain, with liver enlargement and tenderness. right upper quadrant pain, with liver enlargement and tenderness. Elevations of prothrombin time (PT), total bilirubin, and oliguria and Elevations of prothrombin time (PT), total bilirubin, and oliguria and renal function abnormalities may become evident renal function abnormalities may become evident
Stage III (72 to 96 hours)Stage III (72 to 96 hours)
Jaundice, confusion (hepatic encephalopathy), a marked elevation in Jaundice, confusion (hepatic encephalopathy), a marked elevation in hepatic enzymes, hyperammonemia, and a bleeding diathesis hepatic enzymes, hyperammonemia, and a bleeding diathesis hypoglycemia, lactic acidosis, renal failure 25%, deathhypoglycemia, lactic acidosis, renal failure 25%, death
Stage IV (4 days to 2 weeks)Stage IV (4 days to 2 weeks)
Recovery phase that usually begins by day 4 and is complete by 7 days Recovery phase that usually begins by day 4 and is complete by 7 days after overdose after overdose
Paracetamol overdoseParacetamol overdose
The risk of toxicity is best predicted by relating the time The risk of toxicity is best predicted by relating the time of ingestion to the serum of ingestion to the serum paracetamolparacetamol concentration concentration
The dose history should not be used as studies have The dose history should not be used as studies have found no correlationfound no correlation
Peak serum concentrations reached within 4 hrs Peak serum concentrations reached within 4 hrs following overdose of immediate-release preparationsfollowing overdose of immediate-release preparations
May be delayed with extended releases preparations or May be delayed with extended releases preparations or drugs that delay gastric emptying (eg, opiates, drugs that delay gastric emptying (eg, opiates, anticholinergic agents) are coingestedanticholinergic agents) are coingested
Check level at >= 4 hrsCheck level at >= 4 hrs
Paracetamol overdose Paracetamol overdose treatmenttreatment
Activated charcoal within four hours of Activated charcoal within four hours of
ingestion ingestion
May reduce absorption by 50 to 90 May reduce absorption by 50 to 90
percent percent
Single oral dose of one gram per Single oral dose of one gram per
kilogram kilogram
Inhibits absorption of oral methionineInhibits absorption of oral methionine
N-acetylcysteine N-acetylcysteine
Antidote – MOA: Antidote – MOA: a glutathione precursor a glutathione precursor
Limits the formation and accumulation of NAPQI Limits the formation and accumulation of NAPQI
Powerful anti-inflammatory and antioxidant effects Powerful anti-inflammatory and antioxidant effects
IV infusion or oral tablets (also oral methionine)IV infusion or oral tablets (also oral methionine)
150mg/Kg over 15 min; 50mg/Kg over next 4 hrs; 100mg/kg 150mg/Kg over 15 min; 50mg/Kg over next 4 hrs; 100mg/kg
over next 16 hrs up to 36hrsover next 16 hrs up to 36hrs
Beyond 8 hours, NAC efficacy progressively decreases Beyond 8 hours, NAC efficacy progressively decreases
S/Es nausea, flushing, urticaria, bronchospasm, S/Es nausea, flushing, urticaria, bronchospasm,
angioedema, fever, chills, hypotension, hemolysis and angioedema, fever, chills, hypotension, hemolysis and
rarely, cardiovascular collapse rarely, cardiovascular collapse
Paracetamol overdose Paracetamol overdose treatmenttreatment
At the end of NAC infusion, a blood sample should be At the end of NAC infusion, a blood sample should be
taken for determination of the INR, plasma creatinine taken for determination of the INR, plasma creatinine
and ALT. If any is abnormal or the patient is and ALT. If any is abnormal or the patient is
symptomatic, further monitoring is required and symptomatic, further monitoring is required and
advice sought from the NPIS advice sought from the NPIS
Patients with normal INR, plasma creatinine and ALT Patients with normal INR, plasma creatinine and ALT
and who are asymptomatic may be discharged from and who are asymptomatic may be discharged from
medical care. They should be advised to return to medical care. They should be advised to return to
hospital if vomiting or abdominal pain develop or recurhospital if vomiting or abdominal pain develop or recur
Indications for liver Indications for liver transplantationtransplantation
Liver transplantation is life-saving for fulminant hepatic Liver transplantation is life-saving for fulminant hepatic necrosis necrosis
The indications for liver transplantation are:The indications for liver transplantation are:
1 - Acidosis (pH < 7.3), or 1 - Acidosis (pH < 7.3), or
2 - PT > 100 sec 2 - PT > 100 sec
3 - Creatinine > 300 mcg/l 3 - Creatinine > 300 mcg/l
4 - Grade 3 encephalopathy (or worse)4 - Grade 3 encephalopathy (or worse) It is better to contact the local liver transplant centre earlier It is better to contact the local liver transplant centre earlier
than this. than this. Grossly abnormal prothrombin times should trigger referral:Grossly abnormal prothrombin times should trigger referral: PT > 20 sec at 24 hr PT > 20 sec at 24 hr PT > 40 sec at 48 hr PT > 40 sec at 48 hr
Alcohol poisoningAlcohol poisoning
Clinical features of acute alcohol poisoning include:Clinical features of acute alcohol poisoning include:
Ataxia and anaesthesia leading to accidental injury Ataxia and anaesthesia leading to accidental injury
Dysarthria and nystagmus Dysarthria and nystagmus
Drowsiness which may progress to coma Drowsiness which may progress to coma
Inhalation of vomit which can be fatal & should be prevented Inhalation of vomit which can be fatal & should be prevented
Hypoglycaemia in children and some adults Hypoglycaemia in children and some adults
Check BM stix and give 50% glucose i.v. if requiredCheck BM stix and give 50% glucose i.v. if required
Coma (alcohol induced)Coma (alcohol induced) In cases of alcohol induced coma exclude:In cases of alcohol induced coma exclude:
1.1. Coincident head injuryCoincident head injury
2.2. Hepatic failure Hepatic failure
3.3. MeningitisMeningitis
4.4. Wernicke’s encephalopathy Wernicke’s encephalopathy
5.5. Other associated drug ingestionOther associated drug ingestion A blood test will confirm substantial levels of alcohol A blood test will confirm substantial levels of alcohol Rule out alcoholic hypoglycaemiaRule out alcoholic hypoglycaemia The airway and circulation must be maintainedThe airway and circulation must be maintained But glucose- containing fluids may precipitate Wernicke's But glucose- containing fluids may precipitate Wernicke's
encephalopathyencephalopathy Thiamine should given to allThiamine should given to all Intravenous naloxone has reversed coma in a proportion of Intravenous naloxone has reversed coma in a proportion of
casescases